1. Field
A liposome containing cationic lipids, a pharmaceutical composition for the delivery of an anionic drug, and a method for delivering an active agent to a target are provided.
2. Description of the Related Art
A variety of biomaterials including liposomes, polymers, peptides, etc. have been used in drug delivery systems.
Liposomes have at least one lipid bilayer membrane enclosing an aqueous internal compartment. Liposomes may be characterized by membrane type and by size. Given a diameter of 20 nm to 50 nm, liposomes with a single membrane are classified as small unilamellar vesicles (SUV), while large unilamellar vesicles (LUV) have a diameter of greater than 50 nm. Large oligolamellar vesicles and large multilamellar vesicles may have multiple and optionally concentric membrane layers and be larger than 100 nm. Liposomes with several nonconcentric membranes, i.e., several smaller vesicles contained within a larger vesicle, are termed multivesicular vesicles.
A liposome is formulated to carry drugs or other active agents either contained within the aqueous inner space (water-soluble active agents) or partitioned into the lipid bilayer (water-insoluble active agents).
Active agents that have short half-lives in the bloodstream are particularly suited to delivery via liposomes. For example, many anti-neoplastic agents are known to have a short half-life in the bloodstream, and thus their parenteral use is not feasible. However, the use of liposomes for site-specific delivery of active agents via the bloodstream is severely limited by the rapid clearance of liposomes from the blood by cells of the reticuloendothelial system (RES).
A liposome may release part or all of its contents (e.g., “leak”) if a hole is formed in the liposome membrane, if the membrane degrades or dissolves, or if the temperature of the membrane increases to a phase transition temperature. The elevation of temperature at a target site in a subject (hyperthermia) may increase the temperature of the liposome to a phase transition temperature or higher, thereby releasing liposome contents. This process may be applied to selectively deliver therapeutic agents. However, this technique is limited where the phase transition temperature of the liposome is significantly higher than the normal tissue temperature.
After extravasation, liposomes are more apt to be accumulated in tumors thanks to the EPR (enhanced permeation and retention) effect. In this case, the solid cancer-specific targeting efficiency is poor. To overcome this problem, the introduction of a targeting moiety into a liposomal surface has been suggested. Although increasing in tumor accumulation, immunoliposomes, which are designed to have antibodies or antibody fragments conjugated into liposomal surfaces, suffer from the problems associated with antibody construction, namely high production cost and difficult quality control due to poor reproducibility.
Separately, nanocarriers which extravasate drugs in response to internal stimuli have been studied. For example, nanocarriers have been designed to release drugs at low pH or in the presence of specific enzymes on the basis of the features of solid cancer such as low pH around the tumor, or overexpress specific enzymes. However, because these features of solid cancer vary depending on various factors including individual patients, the type and stage of cancer, etc., the nanocarriers taking advantage of these features are limited in universal applications to the treatment of cancer.
There is therefore a need for a carrier that is capable of efficiently delivering active agents.